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PART-I Introduction to Glycerol.
5.1.1 INTRODUCTION:
5.1.2 OBJECTIVE OF THE WORK:
5.1.3 DESIGN AND DEVELOPMENT:
5.1.3.1 Solvent properties of glycerol
5.1.3.2 Limitations
5.1.4 TWELVE PRINCIPAL OF GREEN CHEMISTRY
5.1.5 REFERENCES:
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“It is better to prevent waste than to
treat or clean up waste after it is
formed”
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5.1.1 INTRODUCTION TO GLYCEROL:
Most of the organic reactions occur in a liquid phase. The solvent not only allows a
better contact between reactants, stabilizes or destabilizes intermediates and/or
transition states but also determines the choice of work up procedures and recycling or
disposal strategies. Taking into account the impact of chemical processes on the
environment, the search for innovative concepts for the substitution of volatile organic
solvents has become a tremendous challenge in academia and industry.1 According to
the twelve principles of green chemistry (Table 1), a green solvent should meet
numerous criteria such as low toxicity, non-flammability, non-mutagenicity, nonvolatility and widespread availability among others. Moreover these green solvents
have to be cheap and easy to handle and recycle.2
In the past decade, water,3 ionic liquids,4 polyethylene glycol,5 supercritical fluids6
(particularly supercritical carbon dioxide (scCO2)7) and perfluorinated solvents8
appeared as the most promising approaches for current solvent innovation. Although
fascinating results have been reported, use of these solvents is still subject to strict
limitations such as high cost equipment for scCO2,9 or high prices and lack of data
about the toxicity and bio-compatibility for ionic liquids,10 or product separation for
aqueous-based processes.11 In other words, a universal green solvent doesn’t exist and
for this reason, the scientific community is continuously searching for new sustainable
media in order to widen their use in catalytic and organic processes.
Nowadays, most solvents are prepared from fossil oil reserves. With the predicted
disappearance of oils, interest in utilization of biomass-derived solvents has grown.12
So far, many naturally available products, such as soy methyl ester,13 lactate ester,14 Dlimonene15 and polyhydroxyalkanoates16 among others have been proposed as safer
solvents for catalysis, organic reactions or separations. Many others have also been
used as precursors for the synthesis of potentially safer green solvents, for example,
bio-based ionic liquids.17 As compared to the traditional petrochemical-derived
solvents, these biomass-based solvents exhibit many advantages such as
biodegradability, low vapor pressure and high boiling point which perfectly fit with
the different international legislations pushing forward the reduction of volatile
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organic compounds (VOCs) in the atmosphere. If these biomass-derived solvents are
attractive from the viewpoint of green chemistry, it is also noteworthy that their broad
utilization in industry requires them to be cost profitable which represents a
prerequisite for their viable utilization.
In this context, the possible use of glycerol as a solvent for catalysis or organic
chemistry has become of particular interest. This topic is mainly boosted by the rapid
emergence of biodiesel on the market. Indeed, glycerol is the main co-product of the
vegetable oil industry and new applications are now strongly researched for this
natural polyol.18 Most efforts in this area focus on conversions of glycerol to higher
value-added chemicals and some comprehensive reviews have already summarized
this work.19 Although promising works have been reported, other methods that are
capable of economically utilizing glycerol waste have also to be considered. In
particular, the utilization of glycerol as a solvent or as a precursor for the synthesis of
biomass-based solvents has recently emerged in the literature as a feasible and
promising approach. Even if this topic does not aim to consume glycerol as a reactant,
it is noteworthy that the direct use of glycerol as a solvent offers an indisputable
economically and environmentally viable application for this natural polyol.
In this perspective, we develop a method for the synthesis of N-heterocycle, using
glycerol as solvent in a catalyst free condition.
Water is the first solvent of choice regarding the aforementioned considerations, yet
the negligible solubility of many organic and organo-metallic compounds in water
limits its applications. Using organic, petroleum-based, solvents that allow dissolving
a large variety of solid, liquids, and gases is usually accompanied with air, water, and
land contamination. Fluorous phases20 and ionic liquids21 have been reported as
recyclable environmentally benign reaction media. However, not only that ionic
liquids and perfluorinated solvents are non-biodegradable and toxic, their production
is also associated with use of high amounts of hazardous and volatile organic solvents.
Supercritical fluids and especially supercritical CO2 have also been reported as green
solvents, but their high critical properties still limits their practical use.22
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Glycerol is usually produced as a byproduct of the trans etherification of a triglyceride
in the production of natural fatty acid derivatives. These derivatives are utilized in
many areas from pharmaceuticals and food industry to alternative fuels, e.g.,
biodiesel, and thus as the production of glycerol raises its price decreases. In addition,
glycerol has also promising physical and chemical properties. It has a very high
boiling point and negligible vapor pressure; it is compatible with most organic and
inorganic compounds, and does not require special handling or storage. Glycerol, as
other polar organic solvents such as DMSO and DMF, allows the dissolution of
inorganic salts, acids, and bases, as well as enzymes and transition metal complexes
(TMCs), but it also dissolves organic compounds that are poorly miscible in water and
is non-hazardous. Different hydrophobic solvents such as ethers and hydrocarbons
which are immiscible in glycerol allow removing the products by simple extraction.
Distillation of products is also feasible due to the high boiling point of glycerol.
5.1.2 OBJECTIVE OF WORK:
The purpose of this study is to explore the scope and limitations of glycerol as
alternative green reaction medium. Glycerol, which is a non-toxic, biodegradable, and
recyclable liquid manufactured from renewable sources, shows similar properties as
an ionic liquid and has a high potential to serve as green solvent for organic syntheses.
This has led us to study its possible use as such in a variety of ways. Several noncatalytic and catalytic reactions using homogeneous and heterogeneous chemo- and
bio-catalysts have been thus studied in glycerol. The unique physico-chemical nature
of glycerol enables easy separation of the product by extraction or distillation together
with catalyst recycling. These properties can also be translated into other processes
which require non-aqueous polar solvents such as non-aqueous emulsions,23 as well as
applications in microwave promoted synthesis.24
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5.1.3 DESIGN AND DEVELOPMENT:
Solvents are used daily in numerous industrial processes as reaction medium, in
separation procedures, and as diluters. As reaction medium, solvent are employed to
bring reactants and/or catalysts together and to deliver heat and momentum.25 In
addition, the solvent may also affect activity and selectivity. The choice of the right
solvent; i.e., its chemical, physical, and biological nature, also plays a key role from
environmental, economic, safety, handling, and products isolation point of views.
Considering properties of glycerol as a green solvent we choose it for the synthesis of
nitrogen heterocycles. The points are discussed.
5.1.3.1 SOLVENT PROPERTIES OF GLYCEROL:
In its pure form, glycerol is a sweet-tasting, clear, colorless, odorless and viscous
liquid. Because it is a trihydric alcohol, glycerol is a polar protic solvent with a
dielectric constant of 42.5 (at 25OC) which is intermediate between that of water
(78.5) and an ionic liquid such as 1-buyl-3-methylimidazolium hexafluorophosphate
([BMIm]PF6,11.4). Glycerol is completely soluble in water and short chain alcohols,
sparingly soluble in many common organic solvents (ethyl acetate, dichloromethane,
diethyl ether, etc…), and is insoluble in hydrocarbons. At low temperatures (<17.8,
glycerol forms crystals. Its specific density is 1.26 and its molecular weight is 92.09.
Prior to using glycerol as a potentially safer solvent, some specific points have to be
taken into consideration in order to maximize as much as possible its solvent
properties:
(1)
Solubility:
Like polar solvents such as water, DMSO and DMF, glycerol is able to facilitate
dissolution of inorganic salts, acids, bases, enzymes and many transition metal
complexes. Furthermore, it also dissolves organic compounds that are poorly miscible
in water. Many hydrophobic solvents, such as ethers and hydrocarbons, are
immiscible in glycerol. This enables the reaction products to be removed by simple
liquid–liquid phase extraction.
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Volatility and boiling point:
As mentioned above, glycerol is nonvolatile under normal atmospheric pressure and
has a high boiling point (290OC), thus making distillation of the reaction products a
feasible separation technique. Moreover, taking advantage of its high boiling point,
reactions in glycerol can be carried out at high temperatures, thus allowing
acceleration of the reaction, or making possible reactions that do not proceed in low
boiling point solvents.
(3)
Safety:
Data about the toxicity and environmental compatibility have to be collected before
utilization of a green solvent on a large scale. In this context, glycerol has a clear
advantage compared with most organic solvents. Indeed, glycerol is a nontoxic (LD50
(oral rat)=12600 mg/Kg), biodegradable and nonflammable solvent for which no
special handling precautions or storage is required. In particular, the low toxicity of
glycerol also allows its use as a solvent in the synthesis of pharmaceutically active
ingredients, in which the toxicity and residue of solvents have to be carefully
controlled.
(4)
Availability:
To be viable, a green solvent has to be cheap and available on a large scale. Glycerol
meets these criteria since it is available on a large scale from the vegetable oil
industry. For instance, the production of glycerol reached 1.5 Mt in 2009. Glycerol is
also very cheap (0.50 €/Kg for pharmaceutical grade (99.9%) and 0.15€/Kg for the
technical grade (80%)) and, sometimes, even cheaper than water.
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5.1.3.2 LIMITATIONS:
Despite these clear advantages, the possible use of glycerol as a solvent also requires
chemists to overcome a few obstacles such as:
(1) The high viscosity of glycerol that can induce important mass transfer
problems. Fortunately, at temperatures higher than 60OC, glycerol is much less
viscous. Therefore, reactions involving glycerol as solvent have to proceed at
temperatures higher than 60OC. Otherwise, a fluidifying co-solvent has to be
used.
(2) The chemical reactivity of hydroxyl groups which can lead to the formation of
side products. In particular, the three hydroxyl groups of glycerol are reactive
in extremely acidic or basic conditions. Therefore, glycerol has to be used as a
solvent in a chemically inert environment for the hydroxyl groups to remain
intact.
(3) The coordinating properties of glycerol which may induce some problems
when transition metal complex catalysts are used in this solvent. In particular,
deactivation of organometallic complexes might occur in glycerol.
Taking into account these advantages and disadvantages, research dealing with the
possible use of glycerol as a solvent is no longer a simple transfer of a known method
from a conventional solvent system to glycerol. Therefore, innovative solutions have
to be thought of in order to maximize the advantages of glycerol. Although it seems
very difficult, after a few years of exploration, researchers involved in this field have
developed some successful examples that not only have demonstrated the feasibility
and the necessity of using glycerol as a solvent, but have also contributed to the
emergence of promising methods especially in the field of organic synthesis, catalysis,
separations and materials chemistry. Now, we will show what glycerol as a solvent
contributes to current chemistry.
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5.1.4 TWELVE PRINCIPAL OF GREEN CHEMISTRY:
1. Prevention
It is better to prevent waste than to treat or
clean up waste after it has been created.
2. Atom Economy
Synthetic methods should be designed to
maximise
the
incorporation
of
all
materials used in the process into the final
product.
3. Less
Hazardous
Chemical Wherever practicable, synthetic methods
Synthesis
should be designed to use and generate
substances that possess little or no toxicity
to people or the environment.
4. Designing Safer Chemicals
Chemical products should be designed to
effect
their
desired
function
while
minimising unnecessary whenever possible
and innocuous when used.
5. Safer Solvents and Auxiliaries
The use of auxiliaries substances (e.g.,
solvents or separation agents) should be
made unnecessary whenever possible and
innocuous when used.
6. Design for Energy Efficiency
Energy
requirements
of
chemical
processes should be recognised for their
environmental and economic impacts and
should be minimised. If possible, synthetic
methods should be conducted at ambient
temperature and pressure.
7. Use of Renewable Feedstocks
A raw material or feedstock should be
renewable rather than depleting whenever
technically and economically practicable.
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8. Reduce Derivatives
Unnecessary
derivatization
(use
of
blocking groups, protection/de-protection,
and
temporary
modification
of
physical/chemical processes) should be
minimised or avoided if possible, because
such steps require additional reagents and
can generate waste.
9. Catalysis
Catalytic
reagents
(as
selective
as
possible) are superior to stoichiometric
reagents.
10. Design for Degradation
Chemical products should be designed so
that at the end of their function they break
down into innocuous degradation products
and do not persist in the environment.
11. Real-time
Analysis
Pollution Prevention
for Analytical methodologies need to be
further developed to allow for real-time,
in-process monitoring and control prior to
the formation of hazardous substances.
12. Inherently Safer Chemistry for Substances and the form of a substance
Accident Prevention
used in a chemical process should be
chosen to minimise the potential for
chemical accidents, including releases,
explosions, and fires.
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5.1.5 REFERENCES:
1. Kerton, F. M.; Alternative Solvents for Green Chemistry, RSC Green Chemistry
Series, Series Editors: J. Clark, 2009
2. Capello, C.; Fisher, U.; Kungerbuhler, K.; Green Chem., 2007, 9, 927
3. Li, C. J.; Chen, L.; Chem. Soc. Rev., 2006, 35, 68
4. Plechkova, N. V.; Seddon, K. R.; Chem. Soc. Rev., 2008, 37, 123
5. Chen, J.; Spear, S. K.; Huddleston J. G.; Rogers, R. D.; Green Chem., 2005, 7,
64
6. Brennecke, J. F.; Chem. Ind., 1996, 831
7. Eckert, C. A.; Knutson, B. L.; Debenedetti, P. G.; Nature, 1996, 383, 313
8. Horvath, I. T.; Acc. Chem. Res., 1998, 31, 641
9. DeSimone, J. M.; Hill, C.; Tumas, W. (Ed.), Green ChemistryUsing Liquid and
Supercritical Carbon Dioxide, 2003, Oxford University Press, USA
10. a) Rogers, R. D.; Seddon, K. R.; (Ed.) Ionic Liquids as Green Solvents
progress and prospect, ACS Pub., 2003 b) Coleman, D.; Gathergood, N.;
Chem. Soc. Rev., 2010, 39, 600
11. William, M. N.; (Ed.) Green Solvents for Chemistry-Perspectives and
Practice, 2003, Oxford University Press, USA
12. Rinaldi, R.; Schuth, F.; Chem Sus Chem, 2009, 2, 1096
13. Salehpour, S.; Dube, M. A.; Green Chem., 2008, 10, 321
14. Aparicio, S.; Alcalde, R.; Green Chem., 2009, 11, 65
15. Virot, M.; Tomao, V.; Ginies, C.; Visinoni, F.; Chemat, F.; J. Chromatogr., A,
2008, 147, 1196
16. Reddy, C. S. K.; Ghai, R.; Rashmi; and Kalia, V. C.; Bioresour. Technol.,
2003, 87, 137
17. Imperato, G.; Koenig, B.; Chiappe, C.; Eur. J. Org. Chem., 2007, 1049
18. Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Pina, C. D.; Angew.
Chem., Int. Ed., 2007, 46, 4434
19. a) Jerome, F.; Pouilloux, Y.; Barrault, J.; Chem Sus Chem, 2008, 1, 586 b)
Zhou, C. H.; Beltramini, J. N.; Fan, Y. X.; Lu, G. Q.; Chem. Soc. Rev., 2008,
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37, 527 c) Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Della Pina, C.;
Angew.Chem., Int. Ed., 2007, 46, 4434 d) Behr, A.; Eilting, J.; Irawadi, K.;
Leschinski, J.; Lindner, F.; Green Chem., 2008, 10, 13 e) Pagliaro, M.; Rossi,
M.; The Future of Glycerol: New Usages for a Versatile Raw Material, 2008,
RSC Publishing, Cambridge, UK.
20. Horvath, IT.; Rabai, J.; Science, 1994, 266,72
21. Wasserscheid P, Welton T.; Ionic liquids in synthesis, Wiley,Weinheim, 2003.
22. Jessop, P. G.; Leitner, W.; Chemical synthesis using supercritical fluids, Wiley,
Weinheim 1999
23. Imhof, A.; Pine, D. J.; J Colloid Interface Sci, 1997, 192, 368
24. Kappe, C. O.; Angew Chem Int Ed, 2004, 43,6250
25. Reichardt, C.; Solvent effects in organic chemistry.Verlag Chemie, Weinheim,
1979
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SECTION–I Synthesis of Quinoxaline
SECTION-II Synthesis of Benzoxazole and Benzimidazole
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SECTION-I Synthesis of Quinoxaline
5.2.1 INTRODUCTION:
5.2.2 LITERATURE SURVEY:
5.2.2.1 General method for quinoxaline synthesis
5.2.3 OBJECTIVE OF THE WORK:
5.2.4 DESIGN AND DEVELOPMENT:
5.2.5 EXPERIMENTAL:
5.2.6 RESULT AND DISCUSSION:
5.2.6.1 Mechanism of the reaction
5.2.7 SUMMERY AND CONCLUSION:
5.2.8 REFERENCES:
5.2.9 SPECTRA:
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5.2.1 INTRODUCTION:
The chemistry of heterocyclic compounds has been an interesting field of study for a
long time. Quinoxalines are well known and important N-containing heterocyclic
compound, containing a ring complex made up of a benzene ring and a pyrazine ring,
so called benzopyrazine. It is isomeric with quinazoline, phthalazine and cinnoline.1
Figure 1
Quinoxaline derivatives display a broad spectrum of biological properties (Figure 2)
ranging from DNA cleaving drugs,2 antimicrobial and cancer drugs,3 to antibiotic4 and
antitumor activity.5 Which have made them privileged structures in combinatorial drug
discovery libraries.6 They have also found applications as dyes7 and building blocks in
the synthesis of organic semiconductors,8 and they also serve as useful rigid subunits
in macro cyclic receptors or molecular recognition9 and chemically controllable
switches.10 Therefore, there are constantly new and innovative ideas being developed
to access this important moiety.
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Figure 2
Recently use of glycerol as a sustainable solvent for green chemistry has attracted
more attention. These include Pd-catalyzed Heck and Suzuki cross-couplings, baseand acid- promoted condensations, catalytic hydrogenation, and asymmetrical
hydrogenation. The peculiar physical and chemical properties of glycerol, such as
polarity, low toxicity, biodegradability, high boiling point, and ready availability from
renewable feedstocks,11 prompted us to extend its use as a green solvent in organic
synthesis.
5.2.2 LITERATURE SURVEY:
5.2.2.1 General method for quinoxaline synthesis
A number of synthetic strategies have been developed for the preparation of
substituted quinoxalines. By far, the most common method relies on the condensation
of an aryl 1,2-diamine with a 1,2-dicarbonyl compound in refluxing ethanol or acetic
acid for 2-12 h giving 34-85 % yields.12
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Scheme 5.1-General procedure for the synthesis of quinoxalines
Furthermore, there are several synthetic routes toward quinoxalines, including Bicatalyzed oxidative coupling of epoxides with ene-1,2-diamines, heteroannulation of
nitroketene N, S-aryliminoacetals with POCl3, cyclization of α-arylimino oximes of αdicarbonyl compounds, and from α-hydroxy ketones via a tandem oxidation process
using Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO as well as MnO2.13 Most of the existing
methodologies suffer from disadvantages such as use of volatile organic solvents,
unsatisfactory product yields, critical product isolation procedures, expensive and
detrimental metal precursors and harsh reaction conditions, which limit their use under
the aspect of environmentally benign processes.
1) Coupling of epoxides and ene-1,2 diamines.
The oxidative coupling of epoxides 108 and ene-1,2 diamines 102 in the presence of
Bi(0) and acid derivatives14 is an alternate procedure to access quinoxalines 109
(Scheme 5.2). The reaction is fascinating since epoxides are generally not used to
access quinoxalines although one method using cyano and sulfonyl epoxides has been
reported.15
Scheme 5.2
2) Ammonium
heptamolybdate
tetrahydrate
mediated
synthesis
quinoxaline.
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A. Hasaninejad et al have been reported the synthesis of quinoxalines from aryl 1,2diamines and 1,2-diketones in the presence of ammonium heptamolybdate
tetrahydrate in EtOH/H2O (3/1) at room temperature (Scheme 5.3).16
Scheme 5.3
3) Polyethylene glycol (PEG‐400) mediated synthesis of quinoxalines.
Lingaiah Nagarapu et al have been reported a Polyethylene glycol (PEG‐400)
mediated synthesis of quinoxalines (Scheme 5.4).17
Scheme 5.4
4) Gallium(III) triflate-catalyzed synthesis of quinoxaline.
Jing-Jing Cai et al have been reported a Gallium(III) triflate-catalyzed synthesis of
quinoxaline derivatives (Scheme 5.5).18
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Scheme 5.5
5) Molecular iodine as the catalyst for a one-pot synthesis of quinoxaline.
Rajesh S. Bhosale et al also reported use of molecular iodine as the catalyst for a onepot synthesis of quinoxaline derivatives at room temperature (Scheme 5.6).19
Scheme 5.6
6) Synthesis of quinoxaline under microwave irradiation.
K. Padmavathy et al synthesis of quinoxalines, performed in two stages or as a onepot reaction, starting from ketones via their α-hydroxylimino ketone derivatives, and
condensation of the latter with 1,2- diaminobenzene (Scheme 5.7).20
Scheme 5.7
7) Synthesis of quinoxoline using β-cyclodextrin.
B. Madhav, S et al have been synthesized the various quinoxalines for the first time in
the presence of β-cyclodextrin in water (Scheme 5.8).21
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Scheme 5.8
8) Silica supported synthesis of quinoxaline.
Khodabakhsh Niknam et al reported the synthesis of The reaction of 3mercaptopropylsilica (MPS) and chlorosulfonic acid in chloroform afforded silica
bonded S-sulfonic acid (SBSSA), which was used as a catalyst for the room
temperature synthesis of quinoxaline derivatives from 1,2-diamino compounds and
1,2-dicarbonyl compounds (Scheme 5.9).
Scheme 5.9
9) Proline catalysed synthesis of quinoxaline.
Majid M. Heravi et al also have been reported the synthesis of quinoxaline
Zn[(L)proline] was found to be an effective catalyst for the very fast synthesis of
quinoxaline derivatives from the condensation of the o-phenylenediamines and 1,2dicarbonyl compounds at room temperature (Scheme 5.10).22
Scheme 5.10
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Limitations of Literature methods.
 Use of acid.
 Use of metals
 Create environmental issue
 Generate toxic waste
5.2.3 OBJECTIVE OF WORK:
The purpose of this study is to explore the scope and limitations of glycerol as
alternative green reaction medium. In this sense and due to our interest on green
protocols correlated to the heterocyclic chemistry, we describe herein the use of
glycerol as a green solvent for the preparation of quinoxaline via condensation
reaction.
The previous survey illustrates biological significant of a variety of substituted
quinoxaline which proved to possess wide range of biological activities
On the light of these findings, the present work focuses on the synthesis of certain
quinoxaline derivatives. Hence, a further investigation was adopted to predict the
effect of changing the solvent.
5.2.4 DESIGN AND DEVELOPMENT:
Though there are many methods reported for synthesis of quinoxaline but most of the
methods are having limitations as mentioned in above from environmental point of
view. Therefore still there is broad scope for development of new green method for
the quinoxaline synthesis, so to overcome above mentioned drawbacks. Efforts has
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been done to develop a new green method for direct synthesis of quinoxaline which
can overcome some of the limitations of existing methods in terms of safety, reaction
time, yield, and cost of reagents.
Now, a day glycerol has played a prominent role in the ecological system as green
solvent. We have tried to extend these green properties of glycerol solvent for the
condensation of 1,2 diamine with 1,2 dicarbonyl compounds, and expected that it
could be cyclised by glycerol and can able to give quinoxaline, without applying any
use of acid or any catalyst.
Based on this aspect the model reaction was carried out by using o-phenylenediamine,
and benzil in a glycerol, and reaction was monitored by TLC.
Reaction went to completion after 4 h. After completion of reaction, and work up,
products containing a mixture of compounds were isolated. These compounds were
separated by column chromatography & characterization were carried out by using IR
and NMR techniques and their structure were elucidated as 2,3 diphenylquinoxaline.
The isolated yield was 74% as shown in (Scheme 5.11).
So for our preliminary study, we had successfully developed a simple ecofreindly
method for synthesis of quinoxoline, using very cheap and readily available solvent,
i.e. glycerol. In proposed intensified process all the reaction conditions are feasible
and mild from industrial point of view. All the reagents commercially available and
conditions are easy to handle.
Scheme 5.11
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5.2.5 EXPERIMENTAL:
General procedure for synthesis of quinoxaline derivative:
Table 2, entry 1: 2,3-Diphenylquinoxaline
To a stirred solution of o-phenylenediamine (0.9 mmol, 0.1 gm) in H2O (2 mL),
glycerol (5 ml) was added, and the reaction mixture was heated to 90OC followed by
addition of benzil (0.9 mmol, 0.1 gm). The reaction mixture was stirred vigorously at
90OC. The progress of reaction was monitored by TLC. When all the starting material
had been consumed, the reaction was quenched with water (10 mL) and extracted with
ethyl acetate (2 X 10 mL). The organic phase was separated and dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give crude product. The pure
product was isolated by silica gel column chromatography using (EtOAc: hexane,
1:9); 0.19g (75%).
M. P. 127–128OC (Lit13a m.p: 127OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 8.2 (m,
2H), 7.79 (m, 2H), 7.5 (m, 4H), 7.39 (m, 6H); IR (KBr) (cm-1): 3055, 1541, 1345, 768,
729
Table 2, Entry 2: 6-chloro-2,3-diphenylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.164g, (74%) as White solid; m.p.
124126OC; 1H NMR (60 MHz, CDCl3): δ 8.19-8.15 (m, 1H, ArH), 8.14-8.07 (m, 1H,
ArH), 7.74-7.67 (m, 1H, ArH), 7.55-7.40 (m, 4H, ArH), 7.42-7.30 (m, 6H, ArH); IR
(KBr) νmax/cm-1: 3060, 1544, 1350, 770
Table 2, Entry 3: 6-nitro-2,3-diphenylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.177g, (83%) as yellow powder, m.p.
194-195OC; 1H NMR (CDCl3, 60 MHz): δ 9.08 (d, 1H), 8.53 (m, 1H), 8.30 (d, 1H),
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7.55-7.58 (m, 4H), 7.35-7.44 (m, 6H); IR (KBr) νmax/cm-1: 3439, 1614, 1520, 1397,
1340, 699.
Table 2, Entry 4: 6-methyl-2,3-diphenylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.152g, (63%) as white solid, m.p. 135137OC , 1H NMR (CDCl3, 60 MHz): δ 8.07 (d, 1H), 7.96 (s,1H), 7.50-7.53 (m, 5H),
7.32-7.35 (m, 6H), 2.62 (s, 3H); IR (KBr) νmax/cm-1: 3053, 1615, 1488, 1447, 1341,
670.
Table 2, Entry 5: 2,3-bis(4-methoxyphenyl)quinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.221g, (70%) as white solid, m.p. 148150OC;1H NMR (CDCl3, 60 MHz): δ 8.13 (m, 2H), 7.73 (m, 2H), 7.50 (d, 4H), 6.88
(d, 4H), 3.84 (s, 6H); IR (KBr) νmax/cm-1: 2930, 2836, 1605, 1511, 1344, 1293, 1246,
1173, 833.
Table 2, Entry 6: 2,3-bis(4-methoxyphenyl)- 6-chloroquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.190g, (72%) as Pale yellow solid,
m.p.150-151OC; 1H NMR (CDCl3): δ 3.90 (s, 6H), 6.79 (m, 4H), 7.48-7.57 (m, 4H),
7.72 (m, 1H), 8.10-8.16 (m, 2H); IR (KBr): Vmax cm-1 3442, 3354, 3240, 2913, 1634,
1589, 1562,
Table 2, Entry 7: 2,3-bis(4-methoxyphenyl)-6-nitroquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.189g, (75%) as yellow powder, m.p.
192-193OC; 1HNMR (CDC13, 60 MHz) δ(ppm): 9.1 (d, 1H), 8.49 (m, 1H), 8.24 (d,
1H), 7.56 (m, 4H), 6.98 (d, 4H), 3.9 (s, 6H); IR (KBr) νmax (cm-1): 2924, 1337, 1169,
1021, 835
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Table 2, Entry 8: 2,3-bis(4-methoxyphenyl)-6-methylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.215g, (74%) as White solid, m.p. 126127OC; 1H NMR (CDCl3, 60 MHz): δ 8.00 (d, 1H), 7.90 (s, 1H), 7.46 - 7.56 (m, 5H),
6.87 (d, 4H), 3.83 (s, 6H), 2.59 (s, 3H); IR (KBr) νmax/cm-1: 2925, 2835, 1606, 1343,
1292, 1248, 1175, 833
Table 2, Entry 9: 2,3-di-2-furylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.169g, (70%) as Pale brown solid,
m.p.133-134OC; 1H NMR (CDCl3, 60 MHz): δ 8.12 (m, 2H), 7.72 (m, 2H), 7.61 (s,
2H), 6.66 (d, 2H), 6.55 (s, 2H); IR (KBr) νmax/cm-1: 3103, 1566, 1484, 1397, 1328,
755
Table 2, Entry 10: 6-chloro-2,3-di-2-furylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.149g, (72%) as Brown solid, m.p.125126OC; 1H NMR (60 MHz, CDCl3): δ 8.14-8.00 (m, 2H, ArH), 7.70-7.64 (m, 1H,
ArH), 7.64-7.56 (s, 2H, furan-H), 6.72-6.50 (m, 4H, furan-H);IR (KBr): Vmax cm-1
3108, 1568, 1488, 1399, 1332, 755.
Table 2, Entry 11: 2,3-di-2-furyl-6-nitroquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.150g, (75%) as Orange solid, m.p. 165166OC; 1H NMR (CDCl3, 60 MHz): δ 8.98 (d, 1H), 8.47 (m, 1H), 8.20 (d, 1H), 7.657.68 (m, 2H), 6.85 (m, 2H), 6.60-6.63 (m, 2H); IR (KBr) νmax/cm-1: 3388, 1574,
1522, 1477, 1337, 749
Table 2, Entry 12: 2,3-di-2-furyl-6-methylquinoxaline
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
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general procedure to gave the product with 0.146g, (65%) as Brown solid, m.p.116117OC; 1H NMR (CDCl3, 60 MHz): δ 8.01 (d, 1H), 7.91 (s, 1H), 7.56-7.61 (m, 3H),
6.55 ca. 6.62 (m, 4H), 2.58 (s, 3H); IR (KBr) νmax/cm-1: 3106, 2918, 1485, 1323,
747
Table 2, Entry 13: dibenzo(a,c)phenazine
To a stirred solution of opd (0.1g, 1 equiv., 0.93 mmol.), in glycerol:H2O (5:2 mL)
was added a benzil (0.1g, 1 equiv., 0.9 mmol,) and the remaining procedure same as
general procedure to gave the product with 0.194g, (75%) as white powder, m.p.124126OC; 1H NMR (60 MHz, CDCl3) ppm δ 7.51-7.66 (m, 6H), 8.10-8.13 (m, 2H), 8.33
(d, 2H), 9.18 (d, 2H); IR (KBr): Vmax cm-1 3351, 3228, 2900, 1630, 1578, 1559, 1410
5.2.6 RESULT AND DISCUSSION:
Scheme 5.12
In a model condensation reaction, benzil and 1,2- diaminobenzene in glycerol were
heated at 50OC, (Table 1, entry 2). The progress of the reaction was monitored by
TLC. After completion of the reaction after 8 h, an aqueous work-up afforded 2,3diphenylquinoxaline 2a (50% yield).
To optimise the reaction conditions to afford the desired quinoxoline in good yield,
the same reaction was conducted at different temperature and it was observed that as
slightly increasing temperature, the rate of reaction increases and good amount of
yield was obtained at 90OC within 4 h (Table 1, entry 6). The reaction was
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unsuccessful when carried out at room temperature, even after 24 h (Table 1, entry
1).
To evaluate the use of this procedure, a variety of substituted o-phenylenediamines
were condensed with 1,2-disubstituted 1,2-dicarbonyl compounds. The results are
shown in Table 2. It was observed that the starting materials were consumed after
long reaction time as indicated by TLC analysis. Again the advantage of this protocol
is, after the work-up procedure, glycerol is successfully recovered and reused for
another reaction without affecting the yields.
Next, we also carried out the same reaction in glycerol–methanol mixture and
recovered the desired product in the yield comparable to that obtained in glycerol–
water system. Thus the glycerol–methanol is also a suitable solvent for this
transformation. A variety of aldehydes were condensed with different 1,2 dicarbonyl
compound and the results are summarised in Table 2.
Scheme 5.13
Table 1. Reaction of OPD (1 eqiv.) & benzil (1 eqv.) in glycerol at different rxn. conditions
Entry
Solvent
Rxn.
condition
Time
(h)
Yield
(%)
1
Glycerol
RT
24
NR
2
Glycerol
50Oc
8
50
3
Glycerol:H2O
RT
24
NR
4
Glycerol:H2O
50Oc
8
60
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5
Glycerol:H2O
70Oc
6
68
6
Glycerol:H2O
90Oc
4
75
7
Glycerol:Methanol
90Oc
5
65
Table 2 Reaction of 1,2 diarylamines with 1,2 diketones in presence of glycerola
Time
(h)
Yieldb
%
4
75
2
5
74
3
4
83
4
4
63
5
4
70
6
6
7
4
Entry
1
1,2
Diaminobenzene
1,2 Diketone
Product
72
75
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8
9
10
11
SECTION-I
6
74
5
70
5
72
4
75
5
65
12
13
4
75
a
Reaction conditions: 1,2diamine (1 equiv), 1,2diketone (1equiv). bIsolated yields after column
chromatography and structures were confirmed by comparison of m.p. with authentic materials.
5.2.6.1 Mechanism of the reaction
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Figure 3
5.2.7 SUMMARY AND CONCLUSION:
The chemistry of heterocyclic compounds has been an interesting field of study for a
long time. Quinoxalines are well known and important N-containing heterocyclic
compound, containing a ring complex made up of a benzene ring and a pyrazine ring,
so called benzopyrazine. A number of synthetic strategies have been developed for the
preparation of substituted quinoxalines. Quinoxaline derivatives display a broad
spectrum of biological properties ranging from DNA cleaving drugs, antimicrobial and
cancer drugs, to antibiotic and antitumor activity. Which have made them privileged
structures in combinatorial drug discovery libraries.
In summary, we have described an efficient protocol for preparing quinoxaline
derivatives using glycerol as a solvent. The advantages of the present method lie in
using economic and environmentally benign glycerol as solvent, no use of catalyst,
mild reaction conditions, and good yields. This protocol suitable for large-scale
synthesis, providing a valuable synthetic tool for industrial applications.
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5.2.8 REFERENCES :
1. Brown, D. J.; Taylor, E. C. The Chemistry of Heterocyclic Compounds,
Quinoxalines: Supplement II; Wipf, P., Eds.; John Wiley& Sons: New Jersey,
2004.
2. Toshima, K.; Kimura, T.; Takano, R.; Ozawa, T.; Ariga, A.; Shima, Y.;
Umezawa, K.; Matsumura, S.; Tetrahedron 2003, 59, 7057
3. Sanna, P.; Carta, A.; Loriga, M.; Zanetti, S.; Sechi, L.; IL Farmaco 1998, 53,
455
4. Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K.; Bioorg. Med. Chem. Lett.
2004, 14, 541
5. Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K.; Corbett, T. H.; Horwitz, J.
P.; Bioorg. Med. Chem. 2005, 13, 3910
6. a) Wu, Z.; Ede, N. J.; Tetrahedron Lett. 2001, 42, 8115 b) Lee, J.; Murray, W.
V.; Rivero, R. A.; J. Org. Chem. 1997, 62, 3874 c) Holland, R. J.; Hardcastle,
I. R. Jarman, M.; Tetrahedron Lett. 2002, 43, 6435 d) Krchnak, V.; Smith, J.;
Vagner, J.; Tetrahedron Lett. 2000, 41, 2835 e) Uxey, T.; Tempest, P.; Hulme,
C.; Tetrahedron Lett. 2002, 43,1637 f) Zaragoza, F.; Stephensen, H.; J. Org.
Chem. 1999, 64, 2555
7. a) E.D. Brock, D.M. Lewis, T.I. Yousaf, H.H. Harper, The Proctor and Gamble
Company, WO 9951688, 1999 b) Sonawane, N. D.; Rangnekar, D. W.; J.
Heterocycl. Chem. 2002, 39, 303 c) Katoh, A.; Yoshida, T.; Ohkando, J.;
Heterocycles 2000, 52, 911
8. a) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood, E. L.; J.
Mater. Chem. 2001, 11, 2238 b) O’Brien, D.; Weaver, M. S.; Lidzey, D. G.;
Bradley, D. D. C.; Appl. Phys. Lett. 1996, 69, 881
9. a) Mizuno, T.; Wei, W. H.; Eller, L. R.; Sessler, J. L.; J. Am. Chem. Soc. 2002,
124, 1134 b) Elwahy, A. H. M.; Tetrahedron 2000, 56, 897
10. Crossley, J. C.; Johnston, L. A.; Chem. Commun. 2002, 1122
11. a) Gu, Y.; Jreome, F.; Green Chem. 2010, 12, 1127 b) Pagliaro, M.; Rossi, M.
In The Future of Glycerol: New Usages for a Versatile Raw Material; Clark, J.
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H., Kraus, G. A., Eds.; RSC Green Chemistry Series: Cambridge, 2008 c)
Diaz-Alvarez, A. E.; Francos, J.; Lastra-Barreira, B.; Crochet, P.; Cadierno, V.
; Chem. Commun. 2011, 47, 6208
12. Bhosale R. S.; Sarda S. R.; Ardhapure S. S.; Jadhav W. N.; Bhusare S. R.;
Pawar R. P.; Tetrahedron Lett., 2005, 46, 7183
13. a] Antoniotti, S.; Donach, E.; Tetrahedron Lett., 2002, 43, 3971 b] Venkatesh,
C.; Singh, B.; Mahata, P. K.; IIa, H.; Junjappa, H.; Org. Lett. 2005, 7, 2169 c]
Xekoukoulotakis, N. P.; Hadjiantonious, M. C. P.; Maroulis, A. J.; Tetrahedron
Lett. 2000, 41, 10299 d] Robinson, R. S.; Taylor, R. J. K.; Synlett, 2005, 1003
e] Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K.; Org. Biomol. Chem. 2004, 2,
788 f) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K.; Chem. Commun. 2003,
2286
14. Antoniotti, S.; Dunach, E.; Tetrahedron Lett. 2002, 43, 3971
15. Taylor, E. C.; Maryanoff, C. A.; Skotnicki, J. S.; J. Org. Chem. 1980, 45, 2512
16. Hasaninejada, A.; Zareb, A.; Mohammadizadeha, M. R.; Karamia, Z.; J. Iran.
Chem. Soc., 2009, 6, 153
17. Nagarapua, L.; Mallepallib, R.; Aravab, G.; Yeramanchib, L.; European
Journal Chemistry 2010, 1, 228
18. Cai, J. J.; Zou , J. P.; Pan, X. Q.; Wei, Z.; Tetrahedron Lett., 2008, 49, 7386
19. Bhosale, R. S.; Sarda, S. R.; Ardhapure, S. S.; Jadhav, W. N.; Bhusareb, S. R.;
Pawar, R. P.; Tetrahedron Lett., 2005, 46 , 7183
20. Padmavathy, K.; Nagendrappa, G.; Geetha, K. V.; Tetrahedron Lett., 2011, 52,
544
21. Madhav, B.; Murthy, S. N.; Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D.;
Tetrahedron Lett., 2009, 50, 6025
22. Heravi, M. M.; Tehrani, M. H.; Bakhtiari, K.; Oskooie, H. A.; Catalysis
Commu., 2007, 8, 1341
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5.2.9 SPECTRA:
Table 2, entry 1
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Table 2, entry 1
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Table 2, entry 4
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Table 2, entry 4
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Table 2, entry 3
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Table 2, entry 3
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Table 2, entry 13
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Table 2, entry 13
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SECTION-II Synthesis of Benzoxazole and Benzimidazole
5.2.1 INTRODUCTION:
5.2.2 LITERATURE SURVEY:
5.2.2.1Synthesis of Benzoxazole
5.2.2.2 Synthesis of Benzimidazole
5.2.3 DESIGN AND DEVELOPMENT:
5.2.4 EXPERIMENTAL:
5.2.5 RESULT AND DISCUSSION:
5.2.5.1 Mechanism of the reactions.
5.2.6 SUMMERY AND CONCLUSION:
5.2.7 REFERENCES:
5.2.8 SPECTRA:
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5.2.1 INTRODUCTION:
The main objective of the medicinal chemistry is to synthesize the compounds that
show promising activity as therapeutic agents with lower toxicity. Benzoxazole and
benzimidazole derivatives are very useful compound with well known biological
activity.
Benzoxazoles1and Benzimidazoles,2 are privileged organic compounds due to their
recognition in biological and therapeutic activities (Figure 1). Recent medicinal
chemistry applications of these heterocyclic compounds include 5-lipoxygenase
inhibitor,3a
poly(ADP-ribose)polymerase
(PARP)
inhibitor,3b
factor
Xa(FXa)
inhibitor,3c histamine H1-receptor,3d-f 5-HT3-receptor agonist2,3d HIV reverse
transcriptase inhibitor L-697,695,3g anticancer agent NSC-693638,3h and orexin-1
receptor antagonist SB-3348673i.
Other applications of these compounds include their use as anti-inflammatory,4a
antimicrobial,4b antibacterial,5 and antiviral6a,b agents. So development of general
methods for the synthesis of these compounds is thus highly relevant for drug
discovery.
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Figure 1 Examples of some biologically active compounds
Solvents are used daily in numerous industrial processes as reaction medium, in
separation procedures, and as diluters. As solvents are responsible for a large part of
the waste and pollution generated by chemical processes, a key factor to enabling a
sustainable chemical process is solvent selection. Due to environmental concerns,
safety considerations, reduction of costs, and the simplicity of the process, reactions
using green solvents have drawn great attention in recent years.7
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5.2.2 LITERATURE SURVEY:
5.2.2.1Synthesis of Benzoxazole
To date, three commonly used strategies for the synthesis of 2-substituted
benzoxazoles have been developed. The first approach is through condensation of 2aminophenols with carboxylic acids in the presence of a strong acid at high
temperature.8 The drastic reaction conditions employed therein often cause low yields
and side reactions. The second method is via the oxidative cyclization of phenolic
Schiff
bases
promoted
by
various
oxidants
such
as
2,3-dichloro-5,6-
dicyanobenzoquinone,9a PhI(OAc)2,9b ThClO4,9c PCC,9d I2,9e K2S2O8,9f Pd(OAc)2/O2,9g
HAuCl4•4H2O/O29h and activated carbon/ O2.9i The third approach to 2-substituted
benzoxazoles is the intramolecular cross-coupling of 2-bromoanilides promoted by
copper(I)/(II),10a iron(III) complex,10b or copper(II) oxide nanoparticles.10c These
coupling reactions usually proceed under mild conditions with wide substrate scope.
1) Iron-Catalyzed Intramolecular O-Arylation
Iron-catalyzed intramolecular O-arylation, which represents a practical and
straightforward approach toward 2-aryl substituted benzoxazole derivatives (Scheme
5.1). 11
Scheme 5.1
2) Copper-Catalyzed Synthesis of Substituted Benzimidazoles, and Benzoxazoles
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The synthesis of substituted benzimidazoles, and benzoxazoles is described via
intramolecular cyclization of o-bromoaryl derivatives using copper (II) oxide
nanoparticles in DMSO under air (Scheme 5.2).12
Scheme 5.2
3) Synthesis of 2-arylbenzoxazoles by oxidation with o-iodoxybenzoic acid (IBX)
The preparation of 2-arylbenzoxazoles has been developed based on the oxidation of
phenolic Schiff bases with o-Iodoxybenzoic acid (IBX) (Scheme 5.3).13
Scheme 5.3
4) One-pot synthesis of 2-arylbenzoxazoles using hydrogen tetrachloroaurate as
catalyst under oxygen atmosphere
One-pot synthesis of 2-arylbenzoxazoles, which were directly synthesized from 2aminophenol and aldehydes catalyzed by hydrogen tetrachloroaurate (HAuCl4·4H2O)
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under an oxygen atmosphere with anhydrous tetrahydrofuran (THF) as solvent or in
solvent-free condition (Scheme 5.4).14
Scheme 5.4
5) A Synthesis of 2-Substituted Benzoxazoles via RuCl3·3H2O Catalyzed
Tandem Reactions in Ionic Liquid.
Synthesis of 2-substituted benzoxazoles through RuCl3•3H2O catalyzed, air oxidized
tandem reactions of 2-aminophenols and aldehydes in [bmim]BF4 was developed
(Scheme 5.5).15
Scheme 5.5
6) Phenylboronic acid catalyzed-cyanide promoted, one-pot synthesis of 2-(2-
hydroxyphenyl)benzoxazole derivatives
phenylboronic acid catalyzed, cyanide promoted synthesis of 2-(2-hydroxyphenyl)
benzoxazoles from salicylaldehydes and o-aminophenols is described (Scheme 5.6).16
Scheme 5.6
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5.2.2.2 Synthesis of Benzimidazole
Benzimidazoles have also been synthesized by a number of method and using a
variety of starting material. The reported methods involved the condensation of ophenylenediamine with different substituted aldehydes in the presence of various
transition metal–triflate salts such as Sc(OTf)3 or Yb(OTf)3,17a,b sulphamic acid,17c
H2O2–HCl,17d FeBr3,17e KHSO417f and HfCl417g to afford benzimidazoles. However,
these methods suffer from many drawbacks such as long reaction time, usage of
expensive and corrosive reagent, high temperature with lesser yield products.
1) Copper- and Palladium-Catalyzed Intramolecular Aryl Guanidinylation.
The formation of 2-aminobenzimidazoles via intramolecular C-N bond formation
between an aryl halide and a guanidine moiety can be achieved using either copper or
palladium catalysis (Scheme 5.7).18
Scheme 5.7
2) Ionic liquid mediated synthesis.
A regioselective one-pot synthesis of 2-aryl benzimidazoles, benzoxazoles and
benzthiazoles has been achieved in excellent isolated yields under ambient conditions
using the ionic liquids, 1-butylimidazolium tetraflouroborate ([Hbim]BF4) and 1,3-din-butylimidazolium tetrafluoroborate ([bbim]BF4) as reaction media and promoters
(Scheme 5.8).19
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Scheme 5.8
3) The synthesis of benzimidazoles using air as the oxidant.
Direct one-step synthesis of various benzimidazoles from phenylenediamines and
aldehydes is described using air as the oxidant (Scheme 5.9) .20
Scheme 5.9
4) Synthesis using polymer supported reagent.
Synthesis of Benzimidazole and Benzoxa/(thia)zole Libraries through PolymerSupported Hypervalent Iodine Reagent (Scheme 5.10). 21
Scheme 5.10
5) Cyclodextrin-promoted synthesis of 2-phenylbenzimidazole in water using air
as an oxidant.
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 -Cyclodextrin-promoted conversion of o-phenylenediamine and benzaldehyde to 2phenylbenzimidazole is described using air as an oxidant (Scheme 5.11).22
Scheme 5.11
6) L-Proline catalyzed selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazole.
L-Proline (10 mol %) was found to be a versatile organocatalyst for the selective
synthesis of 2-aryl-1-arylmethyl-1Hbenzimidazoles from a wide range of substituted
o-phenylenediamines and aldehydes (Scheme 5.12).23
Scheme 5.12
7) Microwave-Assisted Synthesis of Benzimidazoles,
Benzothiazoles from Resin-Bound Esters.
Benzoxazoles,
and
Solid-phase synthesis of benzimidazoles, benzoxazoles, and benzothiazoles libraries
by
microwave-assisted
condensation
of
resin-bound
esters
with
1,2-
phenylenediamines, 2-aminophenols, and 2-aminothiophenols was developed
(Scheme 5.13).24
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Scheme 5.13
However, the major drawbacks of these protocols are use of specially made starting
materials, expensive and/or toxic catalyst, and adverse impact on the environment due
to the use of volatile organic solvents.
5.2.2 DESIGN AND DEVELOPMENT:
Honestly, the rationale of this study is to investigate the scope and limitations of
glycerol as alternative green reaction medium. In this sense and due to our interest on
green protocols correlated to the heterocyclic chemistry, we describe herein the use of
glycerol as a green solvent for the preparation of benzoxazole, and benzimidazole via
condensation reaction.
Intended, our preliminary condensation reaction studies, we carried out the reaction
between 2-aminophenol and benzaldehyde using glycerol as a solvent to afford the
desired benzoxazole (Scheme 5.14). A mixture of 2-aminophenol (1.0 mmol) and
benzaldehyde (1.0 mmol) in aqueous glycerol was stirred at room temperature.
Whereas the reaction using o-phenylenediamine instead of 2-aminophenol (Scheme
5.15). The reaction worked well using various substituted aldehydes furnishing the
corresponding benzimidazoles.
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Scheme 5.14
Scheme 5.14
5.2.3 EXPERIMENTAL:
General procedure for synthesis of benzoxazole derivative:
Table 2; entry 1: 2-Phenylbenzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of benzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 102-103OC (Lit25a m.p: 102OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 8.32 (d,
2H), 7.86-7.79 (m, 1H), 7.67-7.53 (m, 4H), 7.44-7.36 (m, 2H); IR (KBr) (cm-1): 3060,
2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020.
Table 2; entry 2: 2-p-Tolylbenzoxazole
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To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-methyl benzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 114-115OC (Lit7 m.p: 118-119OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.5 (m,
2H), 7.76-7.73 (m, 1H), 7.55-7.52 (m, 1H), 7.33-7.28 (m, 4H), 2.40 (s, 3H); IR (KBr)
(cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020.
Table 2; entry 3: 2-p-nitrobenzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-nitro benzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 270-272OC (Lit8 m.p: 266-268OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.567.83 (m, 8H); IR (KBr) (cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194,
1054, 1020.
Table 2; entry 4: 2-p-Chlorobenzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-chlorobenzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 150-152OC (Lit9 m.p: 147OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.08-8.12 (m,
2H), 7.61-7.71 (m, 1H), 7.52-7.46 (m, 1H), 7.44-7.39 (m, 2H), 7.31-7.25 (m, 2H); IR
(KBr) (cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020, 900.
Table 2; entry 5: 2-p-Bromobenzoxazole
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To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-bromo benzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 155-156OC (Lit10 m.p: 157-158OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.16 (m,
2H), 7.84-7.78 (m, 1H), 7.75-7.68 (m, 2H), 7.66-7.59 (m, 1H), 7.45-7.37 (m, 2H); IR
(KBr) (cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020, 600.
Table 2; entry 6: 2-(4-Methoxyphenyl)benzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-methoxy benzaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 97-98OC (Lit6 m.p: 98OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.2 (m, 2H),
7.74-7.71 (m, 1H), 7.55-7.52 (m, 1H), 7.33-7.28 (m, 2H), 7.01 (d, 2H), 3.86 (s, 3H);
IR (KBr) (cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020.
Table 2; entry 7: 2-(Thien-2-yl)benzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of thiophene-2-aldehyde (0.1 gm, 0.92 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 80-82OC (Lit6 m.p: 81-82OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 7.9 (d, 1H),
7.74-7.71 (m, 1H), 7.55-7.52 (m, 2H), 7.34-7.31 (m, 2H), 7.17 (d, 1H); IR (KBr) (cm1
): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020.
Table 2; entry 8: 2-(Furan-2-yl)benzoxazole
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To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of furan-2-aldehyde (0.1 gm, 0.92 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 88-90OC (Lit11 m.p: 89-90OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 7.75 (d, 1H),
7.66 (d, 1H), 7.55 (d, 1H), 7.38-7.33 (m, 2H), 7.27 (d, 1H) 6.60 (m, 1H); IR (KBr)
(cm-1): 3060, 2961, 1552, 1447, 1346, 1319, 1243, 1194, 1054, 1020.
Table 2; entry 9: 2-(1'-phenylethenyl)benzoxazole
To a stirred solution of 2-aminophenol (0.1 gm, 0.92 mmol) in methanol (1 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of cinnamaldehyde (0.1 gm, 0.92 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 85-86OC (Lit12 m.p: 83-85OC);1H NMR (CDCl3, 60 MHz) δ (ppm): 8.6-7.82 (m,
8H), 7.58 (d, 1H), 7.42 (d, 1H); IR (KBr) (cm-1): 3060, 2961, 1552, 1447, 1346, 1319,
1243, 1194, 1054, 1020.
General procedure for synthesis of benzimidazole derivative:
Table 2, entry 10: 2-Phenylbenzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of benzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 294-295OC (Lit25b m.p: 295OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.92 (s,
1H), 8.20 (d, Hz, 2H), 7.68 (d, Hz, 1H), 7.58-7.48 (m, 4H), 7.23 (d, 2H); IR (KBr)
(cm-1): 3421, 3296, 1587, 1512, 1338, 852, 744, 708
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Table 2; entry 11: 2-(p-methylPhenyl)benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-methyl benzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 268-270OC (Lit2 m.p: 269-270OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.90 (s,
1H), 8.00-8.08 (m, 2H), 7.60-7.20 (m, 6H), 2.30 (m, 3H); IR (KBr) (cm-1): 3450,
3300, 1597, 1505, 1342, 850, 750, 690.
Table 2; entry 12: 2-(3-Nitrophenyl)-1H-benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-nitro benzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 321-322OC (Lit3 m.p: 320 oC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 13.27 (bs,
1H), 8.36-8.41 (m, 4H), 7.7 (bs, 1H), 7.57 (bs, 1H), 7.23 (m, 2H); IR (KBr) (cm-1):
3391, 3250, 1540, 1495, 1300, 856, 744, 708
Table 2; entry 13: 2-(4-Chlorophenyl)-1H-benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-chlorobenzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 292-295OC (Lit3 m.p: 291OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.5 (s, 1H),
8.20 (m, 2H), 8.10 (d, 1H), 7.6 (d, 2H), 7.3 (m, 2H), 7.10 (m, 2H); IR (KBr) (cm-1):
3041, 1450, 1402, 1280, 965, 750
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Table 2; entry 14: 2-(4-Bromophenyl)-1H-benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-bromo benzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 296-298OC (Lit3 m.p: 298OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.9 (bs,
1H), 8.10 (d, 2H), 7.74 (d, 2H), 7.6 (m, 2H), 7.20 (m, 2H); IR (KBr) (cm-1): 3466,
3396, 1639, 1594, 1312, 1274, 1084, 764
Table 2; entry 15: 2-(4-Methoxyphenyl)-1H-benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of p-methoxy benzaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 225-226OC (Lit3 m.p: 224OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.7 (s, 1H),
8.00-8.08 (m, 2H), 7.20-7.6 (m, 6H), 3.81 (m, 3H); IR (KBr) (cm-1): 3045, 1480,
1400, 1300, 1080, 985, 760
Table 2; entry 16: 2-(Furan-2-yl)-1H-benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of furfuraldehyde (0.1 gm, 0.93 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 306-308OC (Lit4 m.p: 310-312OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.7
(bs, 1H), 7.94-7.93 (d, 1H), 7.58-7.54 (m, 2H), 7.21-7.18 (m, 2H), 6.74-6.72 (m, 2H);
IR (KBr) (cm-1): 3040, 1490, 1400, 1320, 1100, 980, 760
Table 2; entry 17: 2-(Thien-2-yl)-1H-benzimidazole
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To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of thiophene2-aldehyde (0.1 gm, 0.93 mmol). The reaction mixture was
stirred vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 285-287OC (Lit4 m.p: 288OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.7 (s, 1H),
7.85-7.83 (m, 1H), 7.73-7.69 (m, 1H), 7.57-7.53 (m, 1H), 6.82-7.03 (m, 3H); IR (KBr)
(cm-1): 3045, 1480, 1400, 1300, 1080, 985, 760
Table 2; entry 18: 2-(1'-phenylethenyl)benzimidazole
To a stirred solution of o-phenylenediamine (0.1 gm, 0.93 mmol) in H2O (2 mL),
glycerol (5 mL) was added and the reaction mixture was heated to 90OC, followed by
addition of cinnamaldehyde (0.1 gm, 0.93 mmol). The reaction mixture was stirred
vigorously at 90OC. The progress of reaction was monitored by TLC. After
completion of reaction, the product was isolated as above procedure.
M.p. 201-203OC (Lit5 m.p: 202OC); 1H NMR (CDCl3, 60 MHz) δ (ppm): 12.7 (s, 1H),
7.65-7.8 (m, 3H), 7.47-7.69 (m, 2H), 7.41-7.46 (m, 2H), 7.33-7.39 (m, 1H), 7.24 (d,
1H), 7.16-7.21 (m, 2H); IR (KBr) (cm-1): 3045, 1643, 1588, 1524, 1493, 1422, 1300,
1080, 985, 760 cm-1
5.2.4 RESULT AND DISCUSSION:
For our initial condensation reaction studies, we carried out the reaction between 2aminophenol and benzaldehyde using glycerol as a solvent to afford the desired
benzoxazole (Scheme 5.15). A mixture of 2-aminophenol (1.0 mmol) and
benzaldehyde (1.0 mmol) in aqueous glycerol was stirred at room temperature. It was
observed that the starting materials were consumed after long reaction time as
indicated by TLC analysis.
To optimise the reaction conditions and to afford the desired benzoxazole in good
yield, the same reaction was conducted at different reaction temperature and it was
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observed that as temperature increases, rate of reaction increases and good amount of
yield was obtained at 90OC within 4 h (Table 1; entry 6). Again the advantage of this
protocol is, after the work-up procedure, glycerol is successfully recovered and reused
for another reaction without affecting the yields.
In order to study the effect of solvent on the rate of the reaction, we executed the same
reaction in absence of water, but the yield of the product decreased drastically (Table
1, entry 2). Next, we also carried out the same reaction in glycerol: methanol mixture
and recovered the desired product in the yield comparable to that obtained in glycerol:
water system. Thus the glycerol: methanol is a suitable solvent for this transformation.
A variety of aldehydes were condensed with 2-aminophenol and the results are
summarised in Table 2.
Scheme 5.15: Preparation of 2-arylbenzoxazole
To expand the synthetic scope of this protocol, we carried out the reaction using ophenylenediamine instead of 2-aminophenol (Scheme 5.16). The reaction worked
well using various substituted aldehydes furnishing the corresponding benzimidazoles
in moderate to good yields (Table 2; entries 10–18). In this case Glycerol:water
system works well.
Scheme 5.16: Preparation of 2-arylbenzimidazole
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To study the generality of this new protocol, a variety of aromatic and heterocyclic
aldehydes with various substitution patterns were reacted with 2-aminophenol as well
as o-phenylenediamine under the optimized conditions to give benzoxazoles and
benzimidazoles respectively. As can be seen from Table 1, most of the substrates
afforded good yields of the corresponding benzoxazoles and benzimidazoles.
Heterocyclic aromatic aldehyde compounds were also suitable for this transformation
(Table 1; entries 7, 8, 17, 18) giving moderate yield.
To the best of our knowledge, the dominant mechanism for production of 2phenylbenzoxazole is the oxidative cyclization of phenolic Schiff bases, which are
derived from the condensation of 2-aminophenols and aldehydes. The preparation of
arylbenzoxazoles through the oxidative cyclization of phenolic Schiff bases may
involve three steps. The first step is the condensation between aromatic aldehyde 1
and o-aminophenol 2 to form Schiff base 3. The second step is the five-memberedring formation from 3 to 4. The third step is the cyclisation of 4 to arylbenzoxazole 5.
In steps 1 and 3, water is produced, and in the presence of water, the equilibrium of
the reaction moves backwards. Therefore, removing water and increasing the stability
of 2 under oxidative condition would be beneficial to the reaction yield and hence the
result of 2-aminophenol with aldehyde in a model reaction was good in methanol:
glycerol system rather than glycerol: water system. In the reaction system, a Schiff
base was generated from the condensation between o-aminophenol and aromatic
aldehyde in glycerol.
If we accept the aforesaid mechanism, one can expect the general effect of electron
donating and electron withdrawing groups on the feasibility of the reaction. In this
regard, aromatic aldehydes bearing electron donating groups on the benzene ring
should increase the yield of the reaction while electron withdrawing groups should
have an inverse effect. As we expect, aromatic aldehydes with electron donating
substituents and
p-halogenated aromatic aldehydes afforded 2-phenylbenzoxazole
and 2-phenylbenzimidazole, which furnished comparable yields of the desired
products (Table 2, entries 2, 4-6, 11, 13-15). On the other hand, with electronwithdrawing substituents also give moderate yield of the corresponding 2Development and Application of New Methodologies for Synthesis of Bioactive Molecules
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phenylbenzoxazole and 2-phenylbenzimidazole were obtained (Table 2, entry 3, 12).
In addition, we explored the scope of the reaction with heterocyclic aromatic aldehyde
compounds, and it was also suitable for this transformation (Table 1; entries 7, 8, 17,
18) giving moderate yield.
Further investigation indicates that α, β unsaturated aldehydes are also suitable for this
reaction (Table 1; entries 9, 16) without affecting the geometry of a double bond. In
general, the aromatic aldehydes containing electron-donating substituent react faster
giving better yield as compared to the aromatic aldehydes containing electronwithdrawing substituent.
Table 1. Reaction of OPDa (1 eqiv.) or o-aminophenol b (1 eqiv.) with benzaldehyde(1 eqv.) in
glycerol at different rxn. conditions.
Entry
Solvent
Rxn. condition
Time
(h)
Yield
(%)
1
Glycerol
RT
24
NR
2
Glycerol
50OC
8
50
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3
Glycerol:H2O
RT
24
NRc
4
Glycerol:H2O
50 OC
8
60
5
Glycerol:H2O
70 OC
6
65
2a
70a
4b
80b
6
Glycerol:H2O
O
90 C
NRc= no reaction
Table 2. Reaction of o-aminophenol and 1,2-diaminobenzene with aldehydes in presence of glycerola
1,2
Diaminobenze
ne
Time
(h)
Yieldb
%
4
80
5
75
6
60
4
65
5
4
75
6
6
82
7
5
60
8
6
65
9
5
70
Entry
1
2
3
4
Aldehyde
Product
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10
11
12
13
14
15
16
17
18
PART-II
SECTION-II
2
70
2
75
3
60
3
60
3
60
2
65
4
60
3
55
3
55
a
Reaction conditions: 1,2diamine (1 equiv), aldehydes (1equiv). bIsolated yields after column
chromatography and structures were confirmed by comparison of m.p. with authentic materials.
5.2.5.1 MECHANISMS:
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Figure xx
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5.2.5 SUMMARY AND CONCLUSION:
Furthermore, product isolation and recycling of glycerol were conveniently achieved
by means of liquid–liquid phase extractions with ethyl acetate. These results not only
demonstrated the necessity of using glycerol as a promoting medium for organic
reactions, but also avoided the use of catalyst, thus simplifying the work-up procedure
and consequently increasing the greenness of the synthetic method. Note that in the
case of technical grade glycerol, the presence of residual free fatty acid salts may play
the role of catalyst, thus allowing the reaction to proceed better than in neat water.
Advantages of glycerol for this reaction include
(i)
The non-assistance of acid catalysts, which not only simplifies the work-up
procedure and minimizes the generation of waste, but also allows the use of
acid-sensitive substrates;
(ii)
Easy separation of the reaction products; and
(iii)
No volatile organic solvent was used.
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5.2.6 REFERENCES:
1) For examples, see: a) Easmon, J.; Purstinger, G.; Thies, K.-S.; Heinisch, G.;
Hofmann, J.; J. Med. Chem. 2006, 49, 6343 b) Sun, L.-Q.; Chen, J.; Bruce, M.;
Deskus, J. A.; Epperson, J. R.; Takaki, K.; Johnson, G.; Iben, L.; Malhe, C. D.; Ryan,
E.; Xu, C.; Biorg. Med. Chem. Lett. 2004, 14, 3799 c) Kumar, D.; Jacob, M. R.;
Reynolds, M. B.; Kerwin, S. M.; Bioorg. Med. Chem. 2002, 10, 3997 d) McKee, M.
L.; Kerwin, S. M.; Bioorg. Med. Chem. 2008, 16, 1775 e) Oksuzoglu, E.; TekinerGulbas, B.; Alper, S.; Temiz-Arpaci, O.; Ertan, T.; Yildiz, I.; Diril, N.; Sener-Aki, E.;
Yalcin, I.; J. Enzyme Inhib. Med. Chem. 2008, 23, 37 f) Potashman, M. H.; Bready, J.;
Coxon, A.; DeMelfi, T. M. Jr.; DiPietro, L.; Doerr, N.; Elbaum, D.; Estrada, J.;
Gallant, P.; Germain, J.; Gu, Y.; Harmange, J.-C.; Kaufman, S. A.; Kendall, R.; Kim,
J. L.; Kumar, G. N.; Long, A. M.; Neervannan, S.; Patel, V. F.; Polverino, A.; Rose,
P.; van der Plas, S.; Whittington, D.; Zanon, R.; Zhao, H.; J. Med. Chem. 2007, 50,
4351 g) Huang, S.-T.; Hsei, I.-J.; Chen, C.; Bioorg. Med. Chem. 2006, 14, 6106
2) For examples, see: a) Alamgir, M.; Black, D. St. C.; Kumar, N. Synthesis, Reactivity
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Table 2, entry 2
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Table 2, entry 3
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Table 2, entry 3
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Table 2, entry 10
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Table 2, entry 13
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Table 2, entry 11
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